Cornea Endothelial Cells
Cornea endothelial cells are found at the boundary between the fluid-filled anterior chamber and the clear stroma at the posterior surface of the cornea. These cells are critical for the maintenance of the cornea, especially maintenance of its transparency and prevention of swelling. Improper functioning corneal endothelial cells are the root cause for the majority of corneal transplants. These cells are extremely fragile, and depend on maintaining a high cell population for proper repair mechanisms. If the number of cornea endothelial cells is low, the repair mechanisms may be insufficient to restore the endothelium and maintain the cornea in proper functioning state. Function of the cornea endothelium is restored when the endothelial cells again act as a proper permeability barrier and maintain the cornea in its clear, non-swollen state. The cornea endothelium is labile particularly during cornea storage prior to transplants, and many corneas need to be discarded due to loss of endothelial cells, when the corneas become swollen or lose clarity. Compositions and methods for enhancing and maintaining the human corneal endothelium are limited. See, U.S. Pat. No. 5,051,443.
Lipoxins
Lipoxins are biosynthesized from arachidonic acid. See, Bazan N. G. (2006) In Basic Neurochemistry: Molecular, Cellular and Medical Aspects, 7th edition, G. Siegel, R. W. Albers, S. T. Brady, D. L. Price (eds.), Chapter 33:575-591; and Mattson M. P., Bazan N. G. (2006) In Basic Neurochemistry: Molecular, Cellular and Medical Aspects, 7th edition, G. Siegel, R. W. Albers, S. T. Brady, D. L. Price (eds.), Chapter 35:603-615. Lipoxins are potent mediators of the resolution phase of the inflammatory response and of dysfunctional immunity. See, Serhan C. N., Takano T., Clish C. B., Gronert K., Petasis N. (1999) Adv. Exp. Med. Biol. 469:287-293; and Fiorucci S., Wallace J. L., Mencarelli A., et al. (2004) Proc. Natl. Acad. Sci. USA. 101:15736-15741. Lipoxin A4 and its analogs, including lipoxin A4 epimer 15 (or 15-epi-lipoxin A4), are well known in the art. See, U.S. Pat. Nos. 6,831,186 and 6,645,978; I. M. Fierro et al., “Lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 inhibit human neutrophil migration: Comparisons between synthetic 15 epimers in chemotaxis and transmigration with microvessel endothelial cells and epithelial cells,” Journal of Immunology, vol. 170, pp. 2688-2694 (2003); G. Bannenberg et al., “Lipoxins and novel 15-epi-lipoxin analogs display potent anti-inflammatory actions after oral administration,” Brit. J. Pharma. Vol. 143, pp. 43-52 (2004); and R. Scalia et al., “Lipoxin A4 stable analogs inhibit leudocyte rolling and adherence in the rat mesenteric microvasculature: role of P-selectin,” Proc. Natl. Acad. Sci. USA. vol. 94, pp. 9967-9′972 (1997). Lipoxin A4 and docosahexaenoic acid-derived neuroprotectin D1 (NPD1) are lipid autacoids formed by 12/15 lipoxygenase (LOX) pathways that exhibit anti-inflammatory and neuroprotective properties. Mouse corneal epithelial cells were found to generate both endogenous lipoxin A4 and NPD1. See, K. Gronert et al., A role for the mouse 12/15-lipoxygenase pathway in promoting epithelial wound healing and host defense,” PNAS, vol. 280, pp. 15267-15278 (2005). Lipoxins have been reported to play a role in wound healing in the corneal of the eye. See, K. Gronert, “Lipoxins in the eye and their role in wound healing,” Prostaglandins, Leukotrienes and Essential Fatty Acids, vol. 73, pp. 221-229 (2005). Lipoxin A4 was shown to be formed in the epithelium of healthy and injured corneas, and lipoxygenase (LOX) enzyme activity has been indicated in the cornea of rats and rabbits. In the mouse cornea, lipoxin A4 was found to be generated in the absence of inflammation. In other tissues, lipoxins are predominantly formed during the resolution phase of acute inflammation. (Gronert, 2005). Lipoxin A4 or LOX have not been reported from the cornea endothelial cells, or from any cells of the back of the eye, only from the corneal epithelial cells. See, also, Bazan, N. et al., “Signal Transduction and Gene Expression in the Eye: A Contemporary View of the Pro-inflammatory, Anti-inflammatory and Modulatory Roles of Prostaglandins and Other Bioactive Lipids,” Survey of Opth., Vol. 41, Supp. 2, pp. S23-S34 (1997); Bazan, N. et al., “Arachidonic Acid Cascade and Platelet-Activating Factor in the Network of Eye Inflammatory Mediators: Therapeutic Implications In Uveitis,” Int'l Opth., Vol. 14, pp. 335-344 (1990); and Bazan, N., “Metabolism of Arachidonic Acid in the Retina and Retinal Pigment Epithelium: Biological Effects of Oxygenated Metabolites of Arachidonic Acid,” The Ocular Effects of Prostaglandins and Other Eicosanoids, Pub. Alan R. Liss, Inc., pp. 15-37 (1989
Lipoxin A4 and its analogs have been proposed as a treatment for dry eye, known generically as keratoconjunctivitis sicca and characterized by lack of moisture or lubrication in the eye. See, U.S. Pat. No. 6,645,978; and U.S. Patent Application Pub. No. U.S. 2005/0255144. Dry eye is known to be a separate condition from dry AMD, which is a disease of the back of the eye that involves the death of photoreceptors and RPE cells.